Breast carcinomas represent a heterogeneous group of tumors at the clinical, histopathologic, and molecular levels (Cancer Genome Atlas Network, Nature 490:61-70, 2012). The diversity of breast carcinoma is increasingly reflected in the diversification of therapeutic approaches that are based on appropriate biomarkers. For example, classification by estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and progesterone receptor (PR) is routinely used in clinical practice as a guide for the selection of therapy for breast cancer subjects.
Neoadjuvant chemotherapy (NAC) allows for rapid assessment of treatment chemosensitivity (DeMichele et al., Clin Cancer Res 2015. doi: 10.1158/1078-0432.CCR-14-1760. PubMed PMID: 25712686). The post-treatment pathologic response can be used to determine efficacy of new systemic therapies, and to tailor further treatment that is most appropriate for the particular subject. Pathological complete response (pCR) is an acceptable surrogate associated with long term outcomes, but despite the addition of anti-HER2 therapy (trastuzumab) and even dual anti-HER2 therapy (trastuzumab with pertuzumab or lapatinib), pCR rates remain low in ER+/HER2+ cases compared with ER−/HER2+ disease, as data presented in a NeoSPHERE, NeoALTTO, and TRYPHAENA trial (Schneeweiss et al., Annals of Oncology 24:2278-2284, 2013; Carey, J Clin Oncol 30:1909-1911, 2012; Gianni et al., Lancet Oncology, 13:25-32, 2012). Also, pCR rates are substantially lower in ER+vs. ER-diseases that are HER2−, motivating investigation into other parameters that are mediating response.